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Survival Probability Curves and their Purported Mechanisms of Action

survival probability fallibilism heat shock nrf2 acetylcholine a7 nachr machr

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#1 HighDesertWizard

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Posted 25 December 2015 - 03:37 PM


I believe the path of practice with the greatest probability of success for increasing personal survival probability is one that pays close attention to scientific studies containing survival probability curves with unusually positive results. I established this thread in December of 2015 because of that belief.

 

Many longevity science thought leaders and enthusiasts are focused on "Aging Theories". I'm not. I try very hard not to have a belief about the fundamental causes of aging. At this moment in human history, there are way too many independent variables that can credibly pose as a cause of aging for it to make sense to have such a belief. The odds of misunderstanding, of getting it wrong, are too high for me to feel comfortable assenting to any Aging Theory.

 

On the other hand, there are more and better studies published these days with survival curves in them than ever before. And sometimes the survival curve findings are associated with an independent variable or two or three with a profoundly positive impact on survival probability.

 

Those are the studies worth exploring in depth to understand the underlying physiological, biological, and neurological basis for the positive survival probability findings.

 

Many times, we'll find that for an independent variable positively impacting survival probability there is a confounding variable worth exploring.

 

 

 

When posting a study reference with a survival probability curve (aka, Meier-Kaplan curve), please provide...

  • one or more scientific study snapshot survival curves
  • a reference link to the study containing the snapshot(s)
  • one to three sentences about the
    • animal(s) referenced by the Survival Curve
    • Intervention Method(s) used to the study animals to produce the Survival Curve
    • Biological Mechanism(s) implicated by the Survival Curves

Looking forward to seeing what we might learn...

 

 

 

 

I changed the title of this forum thread from...

 

SMILE of Longevity Learning Log - Mechanism Survival Curves
 
to...
 
Survival Probability Curves and their Purported Mechanisms of Action
 
I will also be rewriting the opening post. I've archived the old opening post as a blog entry here if you'd like to read it.

 

 


Edited by HighDesertWizard, 01 March 2019 - 12:01 PM.
moderated by threadstarter


#2 HighDesertWizard

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Posted 25 December 2015 - 06:28 PM

The Intra-Cellular Biological Mechanism for the survival curves below is NF-kB Cytokine Transcription Inhibition… NF-kB Cytokine Transcription Inhibition can take place within the Cellular Cytoplasm and also within the nucleus after NF-kB Translocation to it. Cytokine Transcription Inhibition can be achieved via multiple Intervention Methods and extra-cellular Biological Mechanisms...

 
Intervention Method : Rapamycin

 

fOu5aEO.png

 

Comparison of three rapamycin dosing schedules in A/J Tsc2 +/- mice and improved survival with angiogenesis inhibitor or asparaginase treatment in mice with subcutaneous tuberous sclerosis related tumors

 

Study Animals : Mice

 

Biological Mechanism : NF-kB Cytokine Transcription Inhibition via Nuclear Translocation Inhibition

 

 
Intervention Method : Metformin

 

There are at least a dozen or two Survival Curves vis-a-vis Metformin shown in a google search

 

cYcxQTR.png?1

 

Metformin intake associates with better survival in ovarian cancer

 

Study Animals : Homo Sapiens

 

[My view of] Biological Mechanism : NF-kB Cytokine Transcription Inhibition, unsure about Nuclear Translocation Inhibition effect

 
I have more of these and will post them later...

 

Edited by HighDesertWizard, 25 December 2015 - 09:44 PM.

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#3 HighDesertWizard

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Posted 26 December 2015 - 09:55 PM

The Intra-Cellular Biological Mechanism for the 3 survival curves below is NF-kB Cytokine Transcription Inhibition... The first two require "Intact Vagal/Splenic signaling". I believe, but am not 100% certain, that this Inhibition occurs after NF-kB Nuclear Translocation via pCREB/c-fos. The Triggering Component of the larger Mechanism is called the Cholinergic Anti-Inflammatory Pathway (CAIP)...
 
 
Intervention Method : Xanomeline, 20 hours and 30 hours Before Lethal Inflammation Administration
 
 
V74LeyC.png
Xanomeline suppresses excessive pro-inflammatory cytokine responses through neural signal-mediated pathways and improves survival in lethal inflammation. A pre-publication, full study text PDF, with many survival curves included, is here. Had, but now can't find, link to Supplement to study. It contains more survival curves.
 
Study Animals : Mice and Rats
 
Biological Mechanism : NF-kB Cytokine Transcription Inhibition requiring "intact Vagal and Splenic signaling" by a Muscarinic M1 receptor agonist

1sE7S6l.png

 
 
Intervention Method : None. Study animal Heart Rate Variability statistical analysis grouping performed 10 years after 24 hour data collection

d8RicwD.png
 
Power-Law Relationship of Heart Rate Variability as a Predictor of Mortality in the Elderly
 
Study Animals : Wild Type Homo Sapiens
 
Biological Mechanism : NF-kB Cytokine Transcription Inhibition, as measured by its Heart Rate Variability (HRV) marker (Background info links below)


Edited by HighDesertWizard, 26 December 2015 - 10:02 PM.


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#4 HighDesertWizard

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Posted 31 December 2015 - 01:31 AM

The two studies below look at the effect of knocking out the nfkb1 gene to create nfkb1-/- study animals. Of special interest... 

  • Both studies find deterioration of functions related to the p50 NF-kB subunit.
  • In another study... p50 is found to be a part of the Telomerase Holoenzyme

Electron microscopy (EM) structures of Tetrahymena telomerase holoenzyme revealed a central location of the relatively uncharacterized p50 subunit. Here we have investigated the biochemical and structural basis for p50 function... In cells, the N-terminal p50 domain assembles a complete holoenzyme that is functional for telomere maintenance, albeit at shortened telomere lengths.

 

 

Intervention Method : Knockout of the nfkb1 subunit of the transcription factor NF-kB (to create nfkb1-/1 study animals)

 

vYD6Ihe.png 
 

Chronic inflammation induces telomere dysfunction and accelerates ageing in mice

 
Study Animals : Mice
 
Biological Mechanism : 1) Chronic inflammation induced by knockout of the nfkb1 gene, 2) Impaired p50 NF-kB subunit was especially implicated.

 

 
Intervention Method : Knockout the Nfkb1 gene to establish nfkb1-/- study animals


[Notice below that the solid black line at the top of survival curves in (B) is not the top of the chart. It's indicating 100% survival of Nfkb1+/+ study animals at 18 months.]

 
11Y6aX7.png
 

 

Loss of Nfkb1 leads to early onset aging

 

Study Animals : Mice
 
Biological Mechanism : 

 

these data show that loss of Nfkb1 leads to early animal aging that is associated with reduced apoptosis and increased cellular senescence. Moreover, loss of p50 DNA binding is a prominent feature of aged mice relative to young. These findings support the strong link between the NF-(B pathway and mammalian aging.

 


Edited by HighDesertWizard, 31 December 2015 - 01:34 AM.


#5 HighDesertWizard

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Posted 09 January 2016 - 07:38 PM

The two graphic figures below are from the same study looking at NF-kB impacts on gonadotropin-releasing hormone (GnRH).

 

 

Intervention Method : Here we show that the hypothalamus is important for the development of whole-body ageing in mice, and that the underlying basis involves hypothalamic immunity mediated by IκB kinase-β (IKK-β), nuclear factor κB (NF-κB) and related microglia–neuron immune crosstalk. Several interventional models were developed showing that ageing retardation and lifespan extension are achieved in mice by preventing ageing-related hypothalamic or brain IKK-β and NF-κB activation.

 

Vp40MUL.jpg

 is2UvSr.jpg

 

Hypothalamic Programming of Systemic Aging Involving IKKβ/NF-κB and GnRH

 
Study Animals : Mice
 
Biological Mechanism : Mechanistic studies further revealed that IKKβ/NF-κB inhibits GnRH to mediate aging-related hypothalamic GnRH decline, and GnRH treatment amends aging-impaired neurogenesis and decelerates aging. In conclusion, the hypothalamus has a programmatic role in aging development via immune-neuroendocrine integration, and immune inhibition or GnRH restoration in the hypothalamus/brain represent two potential strategies for optimizing lifespan and combating aging-related health problems.


Edited by HighDesertWizard, 09 January 2016 - 07:39 PM.


#6 HighDesertWizard

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Posted 12 January 2016 - 07:18 AM

It's said that the diseases of aging are caused by aging. Let's take a look at survival curves for a few specific diseases.

 

 

Intervention Method : NF-κB is a key transcription factor that regulates inflammatory processes. In the present study, we tested the hypothesis that blockade of NF-κB ameliorates cardiac remodeling and failure after myocardial infarction (MI). Knockout mice with targeted disruption of the p50 subunit of NF-κB (KO) were used to block the activation of NF-κB.

 

Ls5ZVSW.png

 

 

Blockade of NF-κB improves cardiac function and survival after myocardial infarction

 
Study Animals : Mice
 
Biological Mechanism : The present study demonstrates that targeted disruption of the p50 subunit of NF-κB reduces ventricular rupture as well as improves cardiac function and survival after MI. Blockade of NF-κB might be a new therapeutic strategy to attenuate cardiac remodeling and failure after MI.



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#7 HighDesertWizard

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Posted 12 January 2016 - 08:08 AM

It's said that the diseases of aging are caused by aging. Let's continue to look at survival curves for a few specific diseases...

 

Two video links below supplement the survival data finding and show NF-kB Blockade dramatically slows its inducing motor neuron death in ALS...

 
 
Intervention Method : In this study, we show that selective NF-κB inhibition in ALS astrocytes is not sufficient to rescue motor neuron (MN) death. However, the localization of NF-κB activity and subsequent deletion of NF-κB signaling in microglia rescued MNs from microglial-mediated death in vitro and extended survival in ALS mice by impairing proinflammatory microglial activation. 
 
qFo28mt.png
 
 
Microglia Induce Motor Neuron Death via the Classical NF-κB Pathway in Amyotrophic Lateral Sclerosis
 
Study Animals : Mice
 
Biological Mechanism :


Highlights

  • NF-κB is activated in ALS, predominantly in microglia
  • [HWD edit... NF-kB inhibition in Astrocytes had no effect on disease progression and survival]
  • Inhibition of microglial NF-κB delays disease progression by 47% in SOD1-G93A mice
  • Inhibition of NF-κB dampens proinflammatory microglial activation
  • Constitutive activation of microglial NF-κB induces pathological hallmarks of ALS

Watch the two videos below and see NF-kB Blockade reduce the Damage done to Motor Neurons...

  • Watch the 25 second Supplement S3 video to see NF-kB killing off motor neurons in microglia.
  • Then compare with what happens when NF-kB is blockaded via IkBa overexpression in video S4.

 


Edited by HighDesertWizard, 12 January 2016 - 08:15 AM.


#8 HighDesertWizard

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Posted 16 January 2016 - 07:10 PM

It's said that the diseases of aging are caused by aging. Let's continue to look at survival curves for a few specific diseases. The focus this time is on Breast Cancer and Tumor Associated Macrophages (TAMs)...

 

 

Intervention Method : None. Study animal tissue was analyzed after the fact for level of TAM infiltration...

 
HdnHXC8.png
 
 

Prognostic Value of Tumor-Associated Macrophages According to Histologic Locations and Hormone Receptor Status in Breast Cancer

 
Study Animals : Homo Sapiens
 
Biological Mechanism : High levels of Tumor Associated Macrophage (TAM) Infiltration

 

High levels of infiltration of intratumoral, stromal and total TAMs were associated with high histologic grade, p53 overexpression, high Ki-67 proliferation index and negative hormone receptor status. Infiltration of TAMs was also correlated with overexpression of vimentin, smooth muscle actin and alteration of β-catenin. Overall, a high level of infiltration of intratumoral TAMs was associated with poor disease-free survival, and was found to be an independent prognostic factor. [from the study abstract]

 

But from other studies we know that TAMs can be "Re-educated" by NF-kB Inhibition...

 

... When NF-κB signaling is inhibited specifically in TAMs, they become cytotoxic to tumor cells and switch to a “classically” activated phenotype... Targeting NF-κB signaling in TAMs also promotes regression of advanced tumors in vivo by induction of macrophage tumoricidal activity and activation of antitumor activity through IL-12–dependent NK cell recruitment.

 


Edited by HighDesertWizard, 16 January 2016 - 07:11 PM.


#9 HighDesertWizard

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Posted 01 July 2017 - 03:20 PM

Sauna bathing is a health habit associated with better hemodynamic function; however, the association of sauna bathing with cardiovascular and all-cause mortality is not known... We performed a prospective cohort study (Finnish Kuopio Ischemic Heart Disease Risk Factor Study) of a population-based sample of 2315 middle-aged (age range, 42-60 years) men from Eastern Finland. Baseline examinations were conducted from March 1, 1984, through December 31, 1989.

 

 

Intervention Method :  Sauna bathing effect on sudden cardiac death (SCD), fatal coronary heart disease (CHD), fatal cardiovascular disease (CVD) assessed over 25 years, analyzed by Sauna Frequency per Week and Sauna Duration per Session.

 

xtaOIKN.png

 

 

Association Between Sauna Bathing and Fatal Cardiovascular and All-Cause Mortality Events

 
Study Animals : Humans
 
Biological Mechanism : This is a fascinating study. There may be one, but I can't think of another study demonstrating that dosing can make a significant difference in longevity effect.

 

This study did not, itself, suggest Anti-Inflammatory Heat Shock Protein 70 (HSP 70) expression to be the biological mechanism that explains the longevity effect. I assume that is the best explanation for the following reasons:

XJpiIbO.png

 

This study is fascinating and makes clear that we are just now beginning to understand the role of HSP 70 in inflammation and how we might leverage that knowledge for longer, healthier lives.

 

 

NUDt7TG.jpg

 


Edited by HighDesertWizard, 02 July 2017 - 12:46 AM.

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#10 HighDesertWizard

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Posted 02 July 2017 - 12:34 AM

"Rats pretreated with electroacupuncture at a specific acupoint that affects the efferent neural circuits of the autonomic nervous system attenuated their systemic inflammatory responses and improved their survival from lethal endotoxin administration."

 

Intervention Method :  

 

 

86t28PP.png

 

Background...

 

Acupuncture is a 5,000-plus-year-old practice that is still widely used in many countries today.7 Accumulating evidence has demonstrated that acupuncture at select acupoints can modulate activities of the ANS. For example, electroacupuncture at Neiguan (Pc-6; located in the groove caudal to the flexor carpi radialis and cranial to the superficial digital flexor muscles) significantly increases vagal activity, as measured by spectral analysis of heart rate variability.8,9 In contrast, electroacupuncture at Hegu (Li-4; located at the junction of the first and second metacarpal bones) increases sympathetic tone, as evidenced by elevation of blood pressure and increased renal and adrenal nerve activities.10,11 Based on these data, we tested the hypothesis that electroacupuncture at specific acupoints could inhibit systemic inflammatory responses and improve survival via  its impact on the ANS in a rat model of sepsis (systemic administration of endotoxin).

 

​Electroacupuncture Improves Survival in Rats with Lethal Endotoxemia via  the Autonomic Nervous System

 
Study Animals : Rats
 
Biological Mechanism : From the study...

 

"Central Muscarinic Receptor, Vagus Nerve, Peripheral Nicotinic Receptor, and Spleen Are Required for the Protective Action of Electroacupuncture

 

The vagus nerve has recently been identified as a major pathway through which immune function is regulated by the central nervous system, which is termed the “cholinergic antiinflammatory pathway.”18 Our results indicated that unilateral (right-sided) cervical vagotomy before lipopolysaccharide challenge significantly attenuated the protective effects of electroacupuncture pretreatment (survival rate: 7/20 vs. 16/20 in sham-operated rats; P = 0.005; TNF-α: P < 0.0001; figs. 5A and B). Systemic treatment with the nicotinic antagonist mecamylamine (survival rate: 4/20; P < 0.001; TNF-α: P < 0.001), but not the muscarinic antagonist atropine methyl nitrate (survival rate: 19/20; P = 0.32; TNF-α: P = 0.65; figs. 5C and D), completely blocked the protective effects of electroacupuncture. Atropine methyl nitrate delivered directly into the brain completely blocked the protective effects of electroacupuncture (survival rate of 6/20 vs. 15/20 in vehicle controls; P = 0.007; TNF-α: P < 0.0001; figs. 5E and F). These results are consistent with an important role of the central muscarinic receptors in modulating peripheral cytokine production.19 Recent work on the anatomical basis of the cholinergic antiinflammatory pathway indicates that the spleen is required for vagus control of inflammation, although the splenic nerve is classified as catecholaminergic.20 In our study, although splenectomy per se significantly reduced serum TNF-α level compared with sham surgery group (P < 0.0001; fig. 5H), which is consistent with a previous study, 21 it did not improve the survival rate of rats challenged with a lethal dose of lipopolysaccharide (P = 0.77; fig. 5G). When electroacupuncture was applied to splenectomized animals, its survival-enhancing effect disappeared (survival rate of 6/20 vs. 17/20 in sham surgery controls; P < 0.0001; fig. 5G). Also, electroacupuncture failed to inhibit serum TNF-α level in splenectomized animals, unlike in intact animals (P = 0.50; fig. 5H)."

 

"Rats pretreated with electroacupuncture at a specific acupoint that affects the efferent neural circuits of the autonomic nervous system attenuated their systemic inflammatory responses and improved their survival from lethal endotoxin administration."

 

I've posted the different slant on a CAP wiring diagram that Kevin Tracey published earlier in 2017 here at Longecity.


Edited by HighDesertWizard, 02 July 2017 - 01:09 AM.

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#11 HighDesertWizard

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Posted 02 July 2017 - 01:19 AM

It's now more important that we take a step back and reflect on how this science of The Inflammatory Reflex (aka, the Cholinergic Anti-Inflammatory Pathway) has changed what we might do to extend healthy longevity. The three graphic figures shown below all appear upthread along with links to the studies they appear in...

 

SPwpVZKh.png



#12 HighDesertWizard

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Posted 30 July 2017 - 04:24 PM

A scientific team has been focused on control of the speed of aging by a mechanism in the hypothalamus. In a 2013 study, it showed that Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH...

 

In 2017, another study has demonstrated that htNSCs (hypothalamic Neural Stem Cells) that are NF-kB / (Ik-Ba) related can control the speed of aging.

 

Intervention Method : (from the study text)... "we asked whether inhibition of the inflammatory response in these cells might help to overcome this survival problem. To do so, we used htNSCs derived from newborn mice that stably expressed dominant-negative IκBα and GFP (IκBα-htNSCs). We have previously shown that these cells are resilient to NF-κB-mediated inflammation, compared to control htNSCs that stably expressed GFP (control-htNSCs)19. We implanted the same number of IκBα-htNSCs or control-htNSCs into the MBH of mid-aged mice. IκBα-htNSCs demonstrated a pronounced improvement in survival (Fig. 3a), showing that around 50% of grafted IκBα-htNSCs were alive, whereas few grafted control-htNSCs were found at two months after implantation.

 
Impact on Survival Probability

 

jkdC5YL.png

From Hypothalamic stem cells control ageing speed partly through exosomal miRNAs
 
Study Animals : Mice
 
Biological Mechanism :

  • There are dozens of studies (including graphic depictions) demonstrating that Ik-Ba degradation in the cytoplasm leads to NF-kB Nuclear Translocation and (many times, Cytokine Transcription). The pic below is just one of the dozens that might have been included in this post.
  • The net practical take-away that I take from the study...
    • Keeping NF-kB from Translocating to the Nucleus in the Hypothalamus can slow aging and hence increase the odds of survival probability.
  • As early as 1996, a study described how Induction and stabilization of I kappa B alpha by nitric oxide mediates inhibition of NF-kappa B

 

 

graphic figure illustrating that Ik-Ba degradation leads to NF-kB nuclear translocation is a part of some online Bio Science Flash Cards one can purchase to study for mid-terms...

hR6MruS.png


Edited by HighDesertWizard, 30 July 2017 - 06:34 PM.


#13 Nate-2004

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Posted 07 August 2017 - 04:44 PM

 

Sauna bathing is a health habit associated with better hemodynamic function; however, the association of sauna bathing with cardiovascular and all-cause mortality is not known... We performed a prospective cohort study (Finnish Kuopio Ischemic Heart Disease Risk Factor Study) of a population-based sample of 2315 middle-aged (age range, 42-60 years) men from Eastern Finland. Baseline examinations were conducted from March 1, 1984, through December 31, 1989.

 

 

Intervention Method :  Sauna bathing effect on sudden cardiac death (SCD), fatal coronary heart disease (CHD), fatal cardiovascular disease (CVD) assessed over 25 years, analyzed by Sauna Frequency per Week and Sauna Duration per Session.

 

xtaOIKN.png

 

 

Association Between Sauna Bathing and Fatal Cardiovascular and All-Cause Mortality Events

 
Study Animals : Humans
 
Biological Mechanism : This is a fascinating study. There may be one, but I can't think of another study demonstrating that dosing can make a significant difference in longevity effect.

 

This study did not, itself, suggest Anti-Inflammatory Heat Shock Protein 70 (HSP 70) expression to be the biological mechanism that explains the longevity effect. I assume that is the best explanation for the following reasons:

XJpiIbO.png

 

This study is fascinating and makes clear that we are just now beginning to understand the role of HSP 70 in inflammation and how we might leverage that knowledge for longer, healthier lives.

 

 

NUDt7TG.jpg

 

 

Can you explain this one in layman's terms? I've been using the sauna to induce HSP but I'm not sure what this means in terms of them causing inflammation and yet being anti-inflammatory, etc. Induction phase, etc..



#14 HighDesertWizard

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Posted 12 August 2017 - 04:13 PM

Can you explain this one in layman's terms? I've been using the sauna to induce HSP but I'm not sure what this means in terms of them causing inflammation and yet being anti-inflammatory, etc. Induction phase, etc..

 
Hi Nate...
  
I've been asking myself that same question. The evidence I've been looking at appears to suggest...

  • HSP 70 is the main HSP implicated in anti-inflammatory activity
  • HSP 70 is also implicated in inflammatory activity
  • HSP 70 phenotype state might depend on macrophage activation state
    • That's the implication of the 2nd study and diagram posted in my last post.

IMO, getting a handle on the science underlying the HSP anti-inflammatory mechanism is emerging as something important.
 
Here's confirmation of its importance from a 2017 study...
 

The effect of passive heating on heat shock protein 70 and interleukin-6: A possible treatment tool for metabolic diseases?

Increasing physical activity remains the most widely publicized way of improving health and wellbeing. However, in populations that benefit most from exercise (EX), adherence is often poor and alternatives to EX are important to bring about health improvements. Recent work suggests a role for passive heating (PH) and heat shock proteins (HSP) in improving cardio-metabolic health. The aim of this study was to investigate the expression of HSP70 and interleukin-6 in response to either EX or PH and the subsequent effect on glucose control. Fourteen males volunteered and were categorized lean (BMI 23.5 ± 2.2 kg·m−2) or overweight (29.2 ± 2.7 kg·m−2) and completed 60 minutes of either moderate cycling at a fixed rate of metabolic heat production (EX) or warm water immersion in 40°C water (PH). Extracellular HSP70 increased from baseline in both conditions with no differences between PH (0.98 ± 1.1 ng·mL−1) or EX (0.84 ± 1.0 ng·mL−1, p = 0.814). IL-6 increased following both conditions with a two-fold increase after PH and four-fold after EX. Energy expenditure increased by 61.0 ± 14.4 kcal·h−1 (79%) after PH. Peak glucose concentration after a meal immediately following PH was reduced when compared with EX (6.3 ± 1.4 mmol·L−1 versus 6.8 ± 1.2 mmol·L−1; p < 0.05). There was no difference in 24-hour glucose area under the curve (AUC) between conditions. These data indicate the potential for thermal therapy as an alternative treatment and management strategy for those at risk of developing metabolic disease where adherence, or ability to EX, may be compromised.

 
Important study results were not reported in the abstract, but appear in the study conclusion, related both to increased and inhibited IL-6 expression. I don't have a handle on what's going on.
 
But there is something I've become clear about--and we all should be clear about because of the overwhelming evidence...
 

Evolution has been establishing mechanisms* in mammals, including in humans, that, when triggered (via different means specific to the mechanism), improves health and increases survival probability odds via NF-kB nuclear translocation and/or inflammatory cytokine expression inhibition

 

*  I've identified and begun to work on understanding 2 mechanisms to date...

  • The Inflammatory Reflex (TIR)
  • The Heat Shock Protein anti-inflammatory stress response

 

-- HDW, 2016

 [2,742]


Edited by HighDesertWizard, 12 August 2017 - 04:59 PM.

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#15 Nate-2004

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Posted 12 August 2017 - 07:55 PM

 

Can you explain this one in layman's terms? I've been using the sauna to induce HSP but I'm not sure what this means in terms of them causing inflammation and yet being anti-inflammatory, etc. Induction phase, etc..

 
Hi Nate...
  
I've been asking myself that same question. The evidence I've been looking at appears to suggest...

  • HSP 70 is the main HSP implicated in anti-inflammatory activity
  • HSP 70 is also implicated in inflammatory activity
  • HSP 70 phenotype state might depend on macrophage activation state
    • That's the implication of the 2nd study and diagram posted in my last post.

IMO, getting a handle on the science underlying the HSP anti-inflammatory mechanism is emerging as something important.
 
Here's confirmation of its importance from a 2017 study...
 

The effect of passive heating on heat shock protein 70 and interleukin-6: A possible treatment tool for metabolic diseases?

Increasing physical activity remains the most widely publicized way of improving health and wellbeing. However, in populations that benefit most from exercise (EX), adherence is often poor and alternatives to EX are important to bring about health improvements. Recent work suggests a role for passive heating (PH) and heat shock proteins (HSP) in improving cardio-metabolic health. The aim of this study was to investigate the expression of HSP70 and interleukin-6 in response to either EX or PH and the subsequent effect on glucose control. Fourteen males volunteered and were categorized lean (BMI 23.5 ± 2.2 kg·m−2) or overweight (29.2 ± 2.7 kg·m−2) and completed 60 minutes of either moderate cycling at a fixed rate of metabolic heat production (EX) or warm water immersion in 40°C water (PH). Extracellular HSP70 increased from baseline in both conditions with no differences between PH (0.98 ± 1.1 ng·mL−1) or EX (0.84 ± 1.0 ng·mL−1, p = 0.814). IL-6 increased following both conditions with a two-fold increase after PH and four-fold after EX. Energy expenditure increased by 61.0 ± 14.4 kcal·h−1 (79%) after PH. Peak glucose concentration after a meal immediately following PH was reduced when compared with EX (6.3 ± 1.4 mmol·L−1 versus 6.8 ± 1.2 mmol·L−1; p < 0.05). There was no difference in 24-hour glucose area under the curve (AUC) between conditions. These data indicate the potential for thermal therapy as an alternative treatment and management strategy for those at risk of developing metabolic disease where adherence, or ability to EX, may be compromised.

 
Important study results were not reported in the abstract, but appear in the study conclusion, related both to increased and inhibited IL-6 expression. I don't have a handle on what's going on.
 
But there is something I've become clear about--and we all should be clear about because of the overwhelming evidence...
 

Evolution has been establishing mechanisms* in mammals, including in humans, that, when triggered (via different means specific to the mechanism), improves health and increases survival probability odds via NF-kB nuclear translocation and/or inflammatory cytokine expression inhibition

 

*  I've identified and begun to work on understanding 2 mechanisms to date...

  • The Inflammatory Reflex (TIR)
  • The Heat Shock Protein anti-inflammatory stress response

 

-- HDW, 2016

 [2,742]

 

 

This is all very mysterious. I wish I knew as well what is going on here. We need way more study in this area for sure.



#16 HighDesertWizard

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Posted 12 August 2017 - 09:48 PM

 

 

Can you explain this one in layman's terms? I've been using the sauna to induce HSP but I'm not sure what this means in terms of them causing inflammation and yet being anti-inflammatory, etc. Induction phase, etc..

 

<< SNIP >>

 

But there is something I've become clear about--and we all should be clear about because of the overwhelming evidence...
 

Evolution has been establishing mechanisms* in mammals, including in humans, that, when triggered (via different means specific to the mechanism), improves health and increases survival probability odds via NF-kB nuclear translocation and/or inflammatory cytokine expression inhibition

 

*  I've identified and begun to work on understanding 2 mechanisms to date...

  • The Inflammatory Reflex (TIR)
  • The Heat Shock Protein anti-inflammatory stress response

 

-- HDW, 2016

 [2,742]

 

 

This is all very mysterious. I wish I knew as well what is going on here. We need way more study in this area for sure.

 

 

Hi Nate... I'm not clear about what you think is mysterious. I've spent some time on this. If you have a specific question, I may, or not, be able to provide study evidence that addresses it.

 

I believe the evidence about HSP70 and its anti-inflammatory benefit is clear enough that I've begun to try to trigger it.

  • On account of the following two studies, it makes sense to learn how to trigger HSP70 optimally.
  • I'm considering purchase of the AVACEN 100. FDA approval is for pain relief only, but we know better that Passive Heating inhibits NF-kB.


#17 Nate-2004

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Posted 13 August 2017 - 02:10 AM

I'm super unclear about how you can do that when there's evidence that it's both anti-inflammatory and inflammatory at the same time. How does that translate into any specific action? The sauna also boosts IGF-1. I've been using the sauna for months now, 4x a week sometimes two sessions of 20 mins back to back separated by about 10 to 15 min cooldown.


Edited by Nate-2004, 13 August 2017 - 02:11 AM.


#18 HaplogroupW

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Posted 15 January 2018 - 06:24 PM

HighDesertWizard-

 

A bit of a digression from the HSP70 theme: given that inflammatory effects of NF-κB is mediated via the NLRP3 inflammasome:

https://www.ncbi.nlm...pubmed/25686493

 

... and that BHB switches it off:

https://www.ncbi.nlm...les/PMC4352123/

 

I've become more convinced fasting and/or ketogenetic would be a powerful intervention. I've experienced the benefit with my own inflammatory condition. When I cycle carbs back in I usually feel it come back. I've posted about this a few times so people who have seen those will think I'm a broken record.  But I'm always suspicious of my own conclusions and would be interested for someone more knowledgeable to falsify or show errors in what might be my simplistic notion. Do you have any opinion?

 

 


Edited by HaplogroupW, 15 January 2018 - 06:25 PM.

  • Informative x 1

#19 HighDesertWizard

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Posted 16 January 2018 - 09:34 PM

 

A bit of a digression from the HSP70 theme: given that inflammatory effects of NF-κB is mediated via the NLRP3 inflammasome:

https://www.ncbi.nlm...pubmed/25686493

 

 

Hi HaplogroupW... Thanks for the reply.

 

Here's an interesting 2014 study related to one of the studies you posted with a depiction of the a7nAchR inhibition of NF-kB. Oh my, it's a Kevin Tracey pic!

 

α7 nicotinic acetylcholine receptor signaling inhibits inflammasome activation by preventing mitochondrial DNA release

 

The mammalian immune system and the nervous system coevolved under the influence of cellular and environmental stress. Cellular stress is associated with changes in immunity and activation of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, a key component of innate immunity. Here we show that α7 nicotinic acetylcholine receptor (α7 nAchR)-signaling inhibits inflammasome activation and prevents release of mitochondrial DNA, an NLRP3 ligand. Cholinergic receptor agonists or vagus nerve stimulation significantly inhibits inflammasome activation, whereas genetic deletion of α7 nAchR significantly enhances inflammasome activation. Acetylcholine accumulates in macrophage cytoplasm after adenosine triphosphate (ATP) stimulation in an α7 nAchR-independent manner. Acetylcholine significantly attenuated calcium or hydrogen oxide-induced mitochondrial damage and mitochondrial DNA release. Together, these findings reveal a novel neurotransmitter-mediated signaling pathway: acetylcholine translocates into the cytoplasm of immune cells during inflammation and inhibits NLRP3 inflammasome activation by preventing mitochondrial DNA release.

 

aqMR8gk.jpg


Edited by HighDesertWizard, 16 January 2018 - 09:38 PM.


#20 Nate-2004

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Posted 20 January 2018 - 04:59 PM

I just cycled back off of keto after nearly 20 days of it. Tough diet especially if you're as hardcore as getting your blood ketone readings up to 3.5. I imagine BHB is helping do a lot. My girlfriend says it changes our chemistry and she seems less affectionate when I'm on keto, which is really weird though I know about how it changes your smell (despite how much electrolytes with salty water I get).



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#21 HighDesertWizard

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Posted 01 March 2019 - 10:57 AM

I've changed the title of this forum thread from...

 

SMILE of Longevity Learning Log - Mechanism Survival Curves
 
to...
 
Survival Probability Curves and their Purported Mechanisms of Action
 
I will also be rewriting the opening post. I've archived the old opening post as a blog entry here if you'd like to read it.
 






Also tagged with one or more of these keywords: survival probability, fallibilism, heat shock, nrf2, acetylcholine, a7 nachr, machr

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